The Molecular Oncology Section of the MTP performs needed experiments to optimize research on lead agents. Examples include mechanism of action studies, validation of biomarkers for animal studies or clinical trials, etc. Dr. Zajac-Kaye and associates have focused on zebularine, a putative orally active DNA methylation inhibitor. Two studies are underway: (1) The Polyoma Middle T antigen transgenic mice have been used to identify an inhibitory effect of Zebularine. We have conducted microarray gene expression profiling of tumors at various timepoints to determine genes with altered expression, and whether patterns of altered expression are due to DNA methylation. Gene expression differences have been confirmed by QRT-PCR and methylation specific PCR is underway to determine if these differences were caused by alterations in DNA methylation. (2) Combination therapies involving Zebularine. We are conducting studies to identify rational combinations, currently centered on Zebularine-HDAC inhibitors in breast and lung cancer cell lines. A synergistic effect of Zebularine and Depsipeptide has been found, using proliferation and colonization assays. The role of p16 in mediating this synergy is under investigation. In vivo studies are planned. Because of toxicity problems with zebularine, these experiments will be finished. Another collaborative project has commenced with Dr. Natasha Caplen to use siRNAs to identify the mechanism of action of drugs of interest in the intramural program. The group is also participating in the Phase I clinical trial of a second compound of intramural interest, 17-DMAG. Dr. Carolyn Best is also conducting preclinical oncology experiments with antibodies to the IGF-1R. Based on the interest of many intramural PIs in antibodies to IGF-1R, we have lead the negotiation of an agreement with Imclone to obtain the A12 antibody, now in Phase I trial. Dr. Best is characterizing that antibody in model systems for chemoresistant breast cancer, pancreatic cancer and lung cancer. She is also characterizing an antibody to IGF-2 made by Dr. Dmitrov in the intramural program as a potential therapeutic.